The design of novel CNS-active muscarinic agonists requires the incorporation of two pharmacophoric groups into the molecule:
a) a basic sp3-nitrogen atom which at pH 7.4 is protonated and mimics the quarternary nitrogen atom in acetylcholine; and
b) an ester functionality, or bioequivalent, to substitute for the acetyl group of the neurotransmitter.
The discovery of a series of five and six membered heteroaromatic rings that can be substituted for the ester functionality has led to numerous muscarinic agents which do not suffer from the hydrolyric instability that has been a serious drawback to acetylcholine mimics (such as arecoline and aceclidine). The attachment or connection of the two pharmacophoric groups has been accomplished using carbon-carbon bonds usually incorporated into a ring. The 1-azabicyclo[2.2.2]octane and 1-azabicyclo[2.2.1]heptane derivatives are examples of this strategy. (Showell, G. A. et al, J. Med. Chem., 1992, 35, 911-916; Street, L. J. et al, J. Med. Chem., 1990, 33, 2690-2697; MacLeod, A. M. et al, J. Med. Chem., 1990, 33, 2052-2059). ##STR2##
The optimal level of potency and efficacy for the prototype muscarinic agent for the treatment of cognitive disorders has not been determined. A series of compounds with a broad range of activity is needed to determine which if any possess a useful level of cholinergic activity. The relative position of the two pharmacophoric groups within the molecule helps to determine the potency and the efficacy of the molecules as muscarinic agents. In relation to the 1-azabicyclo derivatives, F. I. Carrol, J. Med. Chem., 1992, 35, 2184, demonstrated that by increasing the distance between the pharmacophoric groups by moving the basic nitrogen atom further from the ester functionality (1-aza- to 2-azabicyclo[2.2.1]heptane derivative), the muscarinic agonist activity is retained but with less potency. A drawback of these 2-aza- derivatives is the hydrolyric stability of the ester functionality.